Programmed death-1 (PD-1) is a costimulatory molecule that provides an inhibitory signal in T cell activation. Program death ligand-1 (PD-L1) acts as an inhibitor of human T cell responses by binding to its receptor PD-1 to create the tumor microenvironment. This, in turn, results in tumor progression due to tumor immune surveillance. The PD-L1 protein is abundantly expressed in various human cancers, including non-small cell lung cancer (NSCLC). PD-L1-positive lung tumors show significantly lower numbers of tumor infiltrating lymphocytes (TILs) when compared to PD-L1-negative lung tumors, which suggests that PD-L1 expression in tumor cells may contribute to the negative regulation of the antitumor immune response in NSCLC. Furthermore, a high expression of PD-L1 may contribute to poor prognosis and tumor immune escape by suppressing the maturation of tumor infiltrating dendritic cells.
Poor prognosis in NSCLC is associated with the epithelial-mesenchymal transition (EMT), a key process that drives cancer metastasis. The EMT is highly associated with an inflammatory tumor microenvironment in NSCLC and immune activation that coexists with the elevation of multiple targetable immune checkpoint molecules, such as PD-L1. A further association is seen with the increases in tumor infiltration by CD4+Foxp3+ regulatory T cells that display an EMT phenotype. The PD-1/PD-L1 axis therefore plays a crucial role in tumor progression, the EMT, and poor prognosis in NSCLC.
Human papillomavirus (HPV) 16/18 infection is associated with lung cancer development. The HPV16/18 E6 oncoprotein promotes tumor growth and invasion by attenuating the expression of IL-10, TIMP-3, paxillin, and FOXM1. Tumor invasion induced by E6-mediation of these molecules occurs by triggering the EMT. We therefore speculated that the E6 oncoprotein might induce PD-L1 expression, which would induce tumor invasion and confer poor prognosis in NSCLC.
US20110177088 relates to a method of treatment of hematologic malignancies comprising the step of administering to a subject in need thereof a therapeutically effective amount of a ligand of PD1, wherein said ligand of PD1 is selected from the group consisting of PD-L1 or a fragment thereof which binds to PD1, PD-L2 or a fragment thereof which binds to PD1, and an anti-PD1 antibody or a fragment thereof which binds to PD1, and wherein the hematologic malignancy is selected from the group consisting of a chronic lymphocytic leukemia (CLL) of B-cell origin, a small lymphocytic lymphoma (SLL) of B-cell origin, a multiple myeloma, an acute B cell leukemia and a mantle cell lymphoma. US 20130149305 provides a soluble CD80 protein that interacts with programmed death ligand 1 (PD-L1) and thereby inhibiting the interaction of PD-L1 with T-cell expressed programmed death 1 (PD1) receptor, and thus, minimizing PD-L1 mediated immune suppression. The tumor-infiltrating T cells have been found to upregulate immunosuppressive pathways, such as PD-L1, in a paracrine fashion on tumor cells. Particularly, Vamsidhar Velcheti et al. indicates that PD-L1 expression was significantly associated with tumor-infiltrating lymphocytes and a study on patients with non-small cell lung cancer showed that greater PD-L1 protein and mRNA expression is associated with increased local lymphocytic infiltrate and longer survival (Vamsidhar Velcheti et al., Programmed Death Ligand-1 Expression in Non-small Cell Lung Cancer, Laboratory Investigation (2014) 94, 107-116).
Antibody-mediated blockade of PD-L1 can induce a durable tumor regression and prolonged stabilization of disease in patients with NSCLC. The preliminary data showed a positive correlation between the HPV16/18 E6 oncoprotein and PD-L1 expression in a small subset of NSCLC patients. An oncoprotein vaccine, the Lm-LLO-E7 vaccine, suppresses tumor growth in a TC-1 animal model. (Peng X, Hussain S F, Paterson Y. The ability of two Listeria monocytogenes vaccines targeting human papillomavirus-16 E7 to induce an antitumor response correlates with myeloid dendritic cell function. Journal of immunology 2004; 172:6030-8; Gunn G R, Zubair A, Peters C, Pan Z K, Wu T C, Paterson Y. Two Listeria monocytogenes vaccine vectors that express different molecular forms of human papilloma virus-16 (HPV-16) E7 induce qualitatively different T cell immunity that correlates with their ability to induce regression of established tumors immortalized by HPV-16. Journal of immunology 2001; 167:6471-9.)
However, there is a need to further develop a drug effective in immunotherapy.